Recurrent Aphthous Stomatitis (RAS) is a very common ulcerative oral mucosal disease of unknown etiology. Over 100 million Americans experience these painful ulcers at some point in life. The ulcers may reach half inch in diameter and can last several weeks, affecting patients'quality of life. The lack of understanding of the exact etiology and mechanism of ulcer formation in patients afflicted by this very painful condition has hampered the development of effective therapies. In order to plan and implement successful clinical trials leading to the development of better drugs for our patients we must first identify the cause of this disease. Most scientists agree that the immune system is activated in RAS. However, there is no agreement as to what leads to its activation and ultimately to the development of RAS. Modern medicine has identified intense cross-talks between the endocrine and immune system. In particular, growth factors, such as IGF-1 and related biomarkers, have been shown to regulate the immune system and also wound healing. In two separate published population studies we have found a striking overlap in the age distribution of RAS prevalence and circulating levels of these growth factors. These data, however, do not directly associate RAS and serum levels of growth factors within the same individuals. Our central hypothesis is that excessive levels of IGF-1 are the primary source of immune activation and impaired wound healing in RAS patients. The specific objective of this grant application is to identify links between IGF-1 (and IGF-1-related growth factors) levels and RAS prevalence through secondary analyses of existing national data. Specific Aim 1 is to compare the odds of having RAS now vs. having had recent RAS for each increment in circulating growth factors levels (IGF-1, leptin and insulin). Specific Aim 2 is to compare the odds of having vs. not having had a recent history of RAS for each increment in circulating growth factors levels (IGF-1, leptin and insulin). These results will provide the first evidence that the levels of these growth factors are closely associated with the presence of painful aphthous ulcers. The results of these analyses will create the foundation for R01-level clinical and translational research studies focused on growth factors as the primary driving force leading to RAS formation. PUBLIC HEALTH RELEVANCE: Recurrent Aphthous Stomatitis (RAS;also known as canker sores) is a very common and painful disease of unknown cause that occurs primarily during growth. We have noted a remarkable overlap between RAS and certain growth factors that regulate wound healing, suggesting that this could be the pathway through which RAS develops. The identification of the specific mechanism that leads to RAS formation would open the door to the development of more targeted drugs, expected to have fewer side effects and greater efficacy, for patients suffering from this condition.